Apoptosis As A Mechanism For Liver Disease Progession

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Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.
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Semin Liver Dis. 2010 November ; 30(4): 402–410. doi:10.1055/s-0030-1267540.
Apoptosis as a Mechanism for Liver Disease Progression
Maria Eugenia Guicciardi, Ph.D. and Gregory J. Gores, M.D.

Rueben R. Eisenberg Professor of Medicine, Division of Gastroenterology and Hepatology,
College of Medicine, Mayo Clinic, Rochester, MN
Abstract
Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this
injury is often apoptosis, especially by death receptors. Information from experimental systems
demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The
mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but
likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells,
and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase
inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies
implicating Toll-like receptor 9 (TLR9) in liver injury and fibrosis are also of particular interest.
Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs)
could be delivered to this intracellular receptor. These concepts suggest therapy focused on
interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver
diseases.
Keywords
Bcl-2 proteins; caspase inhibitors; death receptors; stellate cells; Toll-like receptor 9
Liver injury is quite common in human disease. Indeed, biomarkers of hepatocyte injury
such as alanine transaminase (ALT) values are universally present in human sera. What
constitutes the normal range for the serum ALT, and therefore, a ‘healthy liver’ is an
unresolved topic 1. However, the mere presence of circulating ALT in man implies low-
levels of hepatocyte injury. It is now widely appreciated that liver injury is accompanied by
liver cell death, often by apoptosis. Indeed, hepatocyte apoptosis is ubiquitous in human
liver diseases (Table 1)2. Given the remarkable regenerative capacity of the liver, loosing a
few liver cells would appear to be inconsequential to health of the organ and organism.
Unfortunately, prolonged hepatocellular injury results in an exuberant wound healing
response, causing hepatic fibrosis, and, in its extreme form, liver cirrhosis. It is hepatic
cirrhosis with its sequela of portal hypertension, end-stage liver disease and hepatocellular
carcinoma that eventually compromises human life in most chronic liver diseases. One of
the pressing unmet needs in clinical medicine is how to prevent, retard, or even reverse
hepatic fibrosis. Therefore, important biomedical questions emanating from these
observations are how does liver injury promote hepatic fibrosis, and is cell death by
apoptosis a pro-fibrogenic process. This contribution to Seminars in Liver Diseases will
address this issue. We will review current information linking apoptosis to fibrosis and
highlight evolving mechanisms which merit further detailed study. This review will be an
update since our past review on this subject 3. Current information continues to imply a
Address for correspondence: Gregory J. Gores, M.D., College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota
55905, Tel.: 507 284 0686, Fax: 507 284, 0762, gores.gregory@mayo.edu.
Guicciardi and Gores Page 2
direct link between hepatocyte apoptosis and liver fibrosis, thereby suggesting that anti-
apoptotic therapies should also be anti-fibrogenic.
Overview of Apoptosis
Apoptosis is a form of cell death characterized by membrane blebbing, shrinkage of the cell,
chromatin condensation, and nuclear fragmentation 4. Fragmentation of the cell into
membrane defined bodies termed apoptotic bodies is a hallmark of apoptosis; in the liver,
these apoptotic bodies were termed councilman bodies for decades until their true
pathogenesis could be easily verified 5. Apoptosis is mediated biochemically by activation
of intracellular zymogens termed caspases, cysteine-dependent aspartate specific protease 6.
These zymogens are themselves activated by proteolytic cleavage at aspartate moieties,
either within special protein complexes (initiator caspases) or by other active caspases
(down stream or effector caspases). The initiator caspase 8 is activated by induced proximity
and dimerization of the proform within a death receptor complex 7, whereas procaspase 9 is
activated by recruitment to and assembly within a large protein complex termed the
apoptosome 6. The activating cleavage of effector caspases 3 and 7 by initiator caspases
(i.e., caspase 8 or 9) generates a neoepitope which can be identified by
immunohistochemical techniques in liver tissue specimens 8. Likewise caspase cleavage of
cytokeratin 18 also generates a neoepitope which is released into the serum and can be
measured by enzyme-linked immunosorbent assay (ELISA, M30 assay) as an index of
hepatocyte apoptosis 9. Effector caspases are responsible for activating CAD (caspase-
activated DNase) by cleaving ICAD (inhibitor of caspase-activated DNase)10. CAD
activation results in DNA cleavage at internucleosomal linker regions causing the classic
ladder pattern of DNA fragments (multiples of the 180 base pair nucleosomal regions).
DNA cleavage during apoptosis is the basis for the TUNEL (terminal deoxynucleotidyl
transferase dUTP nick end labeling) assay, a method for detecting DNA fragmentation by
labeling the terminal end of nucleic acids. Thus, apoptosis can be readily identified by its
biochemical biomarkers, and this information can be used to explore the relationship
between hepatocyte apoptosis and liver fibrosis.
Mechanisms of Hepatocyte Apoptosis

Apoptosis is a process required to maintain tissue homeostasis and health by
counterbalancing cell proliferation and eliminating damaged and/or aged cells. This is
particularly crucial in an organ like the liver which is naturally exposed to toxins and viruses
11. Any alteration in the balance between proliferation and cell death, by either excessive or
insufficient apoptosis, invariably leads to a pathologic condition. In the liver, massive
hepatocyte apoptosis results in acute liver failure, whereas persistent hepatocyte apoptosis is
often associated with fibrogenesis, chronic liver dysfunction, and even cancer development
12.
Apoptosis can be triggered by a variety of intra- and extra-cellular stimuli. The intracellular
stimuli, such as DNA damage, generally result in mitochondrial outer membrane
permeabilization (MOMP) and release of pro-apoptotic factors, including cytochrome c,
second mitochondria-derived activator of caspases (SMAC)/direct IAP-binding protein with
low PI (DIABLO), and apoptosis-inducing factor (AIF), from the intermembrane space into
the cytosol. This signaling cascade, known as the mitochondrial (or intrinsic) pathway of
apoptosis, is initiated by the activation of pro-apoptotic BH3-only (i.e., Bid, Bim, Bad,
PUMA, Noxa) and multi-domain (Bax and Bak) members of the Bcl-2 family, which are
responsible for the induction of MOMP 13, and antagonized by the anti-apoptotic members
of the same family (Bcl-2, Bcl-xL, Mcl-1) 14. Released cytochrome c associates with
apoptotic protease activating factor 1 (Apaf-1) to form the apoptosome, a large multimeric

complex which recruits procaspase 9 and facilitates its autoactivation 6. Caspase 9 then
cleaves and activates caspase 3 and 7, which, in turn, proceed to degrade several cellular
substrates, resulting in the morphological changes associated to apoptosis. At the same time,
endogenous cellular inhibitors of apoptosis proteins (IAPs), normally inhibiting accidentally

activated caspases, are neutralized by SMAC/DIABLO, which is released from the
mitochondria together with cytochrome c 15.
The extracellular stimuli signal through the engagement of death receptors on the plasma
membrane by their cognate ligands, and the formation of a large death-inducing signaling
complex (DISC)16. This pathway is referred to as the extrinsic pathway of apoptosis. Four of
these death receptors, Fas, tumor necrosis factor receptor 1 (TNF-R1) and death receptor 4
and 5 (DR4 and DR5, also know as TNF-related apoptosis-inducing ligand receptor 1 and 2,
TRAIL-R1 and TRAIL-R2), as well as their ligands, Fas ligand (FasL), TNF-α and TRAIL,
are abundantly expressed in the liver 17, and their signaling cascades have been extensively
studied over the years. Despite some differences in adaptors and other proteins recruited to
their respective DISC, one common event occurring after the stimulation of all death
receptors is the recruitment of the adaptor Fas-associated protein with death domain
(FADD) and procaspase 8, which results in its autoactivation 7. Subsequently, caspase 8 can
either directly cleave and activate caspase 3 and 7 (type I cells, such as lymphocytes)
similarly to caspase 9, or can engage the mitochondrial pathway by cleaving the BH3-only
protein Bid (type II cells, such as hepatocytes), whose truncated fragment translocates to the
mitochondrial outer membrane causing MOMP 18,19. Therefore, the intrinsic and extrinsic
pathways are not mutually exclusive, with Bid mediating the crosstalk between the two
pathways in type II cells.
Because of the ubiquitous expression of death receptors and ligands in liver cells, apoptosis
in the liver is generally mediated by the extrinsic pathway. In particular, activation of Fas
and TNF-R1 is associated with hepatocyte apoptosis in a wide variety of liver diseases,
including viral hepatitis, fulminant hepatic failure, cholestatic liver disease, alcoholic
hepatitis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis
(NASH), Wilsons' disease and ischemia-reperfusion injury 20. For example, during viral
infection, the liver damage is only marginally caused by a cytopathic effect of the virus
itself, but rather due to the infiltrating FasL-expressing cytotoxic T lymphocytes (CTL)
which eliminate the infected hepatocytes by engaging Fas on the hepatocyte surface. CTL
also induce hepatocyte apoptosis via the TNF-TNF-R1 system, and secretion of the
cytotoxins perforin and granzyme 21. In cholestasis, elevated intracellular concentrations of
toxic bile salts result in increased Fas density on the plasma membrane and ligand-
independent activation of the receptor 22,23, as demonstrated by the absence of liver injury in
Fas-deficient mice, but not FasL-deficient mice, after bile duct ligation (a model of
extrahepatic cholestasis). Toxic bile salts are also known to up-regulate DR5 expression,
therefore increasing sensitivity to TRAIL-mediated apoptosis 24. Elevated Fas and FasL are
also features of alcoholic liver injury 25. Moreover, alcohol promotes Kuppfer cells
activation and TNF-α production, and increases the sensitivity of hepatocytes to TNF-α-
mediated apoptosis 26. Fas-mediated hepatocyte apoptosis is also increased in patients with
NASH, and correlates with the progression of the disease from simple steatosis to
steatohepatitis 27. However, liver injury during NASH is not only due to activated death
receptors. Free fatty acids (FFAs) accumulating in the liver as a consequence of insulin
resistance also induce cell death, a process referred to as lipoapoptosis. In particular,
excessive FFAs accumulate in the endoplasmic reticulum (ER), resulting in ER stress.
Saturated FFAs induce Bim expression and phosphorylation 28, JNK-mediated PUMA
expression and Bax activation 29,30, resulting in MOMP as well as lysosomal
permeabilization 31. Moreover, concentrations of FFAs too low to induce lipoapoptosis have

been shown to up-regulate DR5 expression and increase sensitivity of hepatocytes to

TRAIL-mediated apoptosis 32.
Apoptosis and Liver Fibrosis

Several human studies have linked apoptosis to fibrosis. For example, the magnitude of
apoptosis correlates with stage of fibrotic disease in non-alcoholic steatohepatitis
(NASH)27,33, and in fibrosis progression in recurrent hepatitis C (HCV) following liver
transplantation33. Although these human studies are correlative, experimental models more
mechanistically link hepatocyte apoptosis to fibrosis. Mice deficient in Fas display reduced
hepatic fibrosis following bile duct ligation 34. Reduction of hepatocyte apoptosis with a
caspase inhibitor also repressed hepatic fibrosis in this rodent model of cholestatic liver
injury 8. Although these observations could be explained by the potential pro-inflammatory
effects of Fas-mediated liver injury, which require caspases 35,36, other data suggest
hepatocyte apoptosis alone is sufficient to elicit a pro-fibrogenic response in the liver. The
anti-apoptotic members of the Bcl-2 family of proteins are the guardians of the
mitochondrial pathway of cell death 37. The hepatocyte depends upon two such proteins for
survival, Bcl-xL and Mcl-1 38. Hepatocyte-specific deletion of either protein results in
hepatocyte apoptosis, elevation of the serum ALT values and hepatic fibrosis 39,40. These
data are quite remarkable because they appear to be pure models of hepatocyte apoptosis yet
they recapitulate many facets of human liver disease. Moreover, these findings also suggest
the hepatocyte is constitutively undergoing pro-apoptotic stress, even in the absence of

disease, an observation consistent with the presence of ALT in the serum of even healthy
human subjects. Thus, the question is not if apoptosis contribute to progressive liver injury,
but how? There are two broad mechanisms by which apoptotic hepatocytes beget hepatocyte
fibrosis: 1) engulfment of apoptotic bodies is pro-fibrogenic; 2) apoptotic cells release pro-
fibrogenic mediators. These concepts are not mutually exclusive and likely both are
operational in human liver disease.
Apoptotic Bodies and Their Engulfment

Apoptotic bodies are eliminated from the body by cellular engulfment 41. If not eliminated,
the cellular membrane defining the apoptotic body becomes permeant, releasing cellular
constituents into the extracellular space eliciting an inflammatory response, a phenomenon
termed secondary necrosis 41. In massive liver injury, the ability of phagocytic cells to
identify and clean up all the apoptotic bodies is likely overwhelmed, and this process could
explain liver failure and inflammation despite an initial apoptotic stimulus, such as liver
injury by Fas stimulation 42. In order to undergo engulfment, the apoptotic cell must
generate two cells signals, a “find me” signal and an “eat me” signal. One recognized “eat
me” signal is the translocation of phosphatidylserine from the inner (cytoplasmic) leaflet of
the plasma membrane to the outer (cell surface) leaflet, which results in engulfment of the
apoptotic bodies by phagocytic cells 10. In the liver, both hepatic stellate cells (HSC), the
pericytes of the sinusoids, and Kupffer cells, the resident macrophages of the liver, can
phagocytose apoptotic bodies (Fig. 1) 43-45.
Apoptotic Bodies and The “Find Me” Signal

Recent information suggests that apoptotic cells release the nucleotides ATP and UTP into
the extracellular space 46. These chemical mediators have been termed the scent of death 47.
ATP and UTP bind to purinergic receptors on macrophages and HSC, especially the P2Y2
receptor 46. The binding to macrophages serve as a chemoattractant recruiting these
professional phagocytic cells to the site of the dying cell. As P2Y2 receptors are also present
on HSC 48, release of nucleotides by apoptotic hepatocytes is likely an additional
mechanism by which apoptosis promotes hepatic fibrosis. Indeed, ATP and UTP released

from apoptotic cells may function to recruit HSC to sites of liver injury and promote their
activation to myofibroblasts (Fig. 1). Other chemoattractants released from apoptotic cells
include fractalkine, adenosine and the lipid lysophosphatidylcholine41,49. Both compounds
also serve as ligands for G-protein coupled receptors and also likely contribute to HSC
activation in liver injury. Although a role for lysophosphatidyl choline has not been explored
in liver fibrosis, fractalkine has been linked to hepatic inflammation and fibrosis and merits
further attention as a chemokine promoting liver fibrosis by apoptotic cells 50,51.
Apoptotic Bodies and Liver Indigestion

Apoptosis in development is a non-inflammatory process responsible for removing excess
cells in a spatial-temporal sequence. In contrast, apoptosis in pathologic conditions is not
controlled and can be deleterious to the organ and the entire organism 52. Apoptotic bodies
and their engulfment are a major source of this hepatic “indigestion”. For example,
hepatocyte inflammation is a major driving force for hepatic fibrogenesis 53. Apoptosis
contributes to inflammation by promoting Kupffer cell activation. Following engulfment of
apoptotic bodies, Kupffer cells express the death ligands TNF-α, TRAIL and FasL 43,54
(Fig. 1) which may exert a pro-inflammatory effect in this context 55. All these death ligands
have cognate receptors on hepatocytes and may induce death receptor-mediated apoptosis
further aggravating liver injury. Thus, engulfment of apoptotic bodies by Kupffer cells is
likely an important pro-fibrogenic mechanism in liver disease.
In the liver, as in other organs, activated myofibroblasts generate collagen and are
responsible for organ scarring. Myofibroblasts are derived from portal fibroblasts and
hepatic stellate cells 56,57. Whatever their lineage, activated myofibroblasts are phagocytic
and capable of engulfing apoptotic bodies 44,45,58,59. When activated myofibroblast cell
lines engulf apoptotic bodies derived from hepatocytes, they produce profibrogenic
cytokines (such as TGF-β) and type I collagen 44. The engulfment of apoptotic bodies also
results in up-regulation of NADPH oxidase, an enzyme which generates oxygen free
radicals 59. These data help link apoptosis to oxidative stress, which is frequently implicated
as a mechanism contributing to hepatic injury.
If engulfment of apoptotic bodies is pro-fibrogenic, what in the apoptotic bodies is

responsible for this phenomenon? Apoptotic bodies contain micronuclei, a source of DNA.
Unmethylated cytosine-phosphate guanosine (CpG)-DNA motifs are recognized by Toll-like
receptor 9 (TLR 9) (Fig. 2). Indeed, denatured DNA from apoptotic cells is a ligand for TLR
9 60,61 and TLR 9-deficient mice display reduced hepatic injury and fibrosis following liver
injury by carbon tetrachloride, bile duct ligation, acetaminophen, and a model of fatty liver
disease 60-62. The engulfment of the apoptotic DNA would permit access of the CpG-DNA
ligand to the intracellular TLR9 where it would, in turn, activate a variety of signaling
cascades resulting in myofibroblast generation of collagen 1 and the pro-fibrogenic cytokine
TGF-β 63 (Fig. 2). Although TLR9 is thought to be restricted to dendritic cells in humans,
Watanabe et al. demonstrated that, in human stellate cells, CpG oligonucleotides induced
up-regulation of TGF-β and collagen 1 mRNA, and that these effects were blocked by TLR9
antagonists 60. These very important data link apoptosis to activation of the innate immune
response within myofibroblasts.
Apoptosis and Anti-Fibrogenic Strategies for Human Liver Disease

The most direct therapeutic strategy for repressing liver fibrosis is to eliminate the cause for
the liver injury. This has proven clinically possible for viral hepatitis where direct and
indirect anti-viral therapies are quite effective. However, effective treatments do not exist
for many liver diseases such as primary sclerosing cholangitis, NASH, alcohol-mediated
hepatitis, and patients with HCV or HBV unresponsive to antiviral therapies. For such

patients, anti-apoptotic and anti-fibrogenic strategies have a hepatoprotective role. Two

therapeutic strategies emanating from this review include caspase inhibitors and TLR9
receptor antagonists (Fig. 3).
Small molecule caspase inhibitors are attractive for the treatment of human liver diseases.
Indeed, caspase inhibitors attenuate hepatic injury and fibrosis in pre-clinical models of
cholestasis and non-alcoholic liver disease 8,64. More importantly, in a human trial a pan-
caspase inhibitor reduced serum ALT values in patients with HCV without affecting viral
replication 65,66. This agent also attenuates liver ischemia/reperfusion injury in rodents and
man during organ transplantation 67,68. Although there is a concern that apoptosis inhibition
by caspase inhibitors would promote carcinogenesis, we view this as unlikely. There are two
major apoptotic pathways, an extrinsic or death receptor-mediated pathway and an intrinsic
or mitochondrial pathway, as described above. Although the mitochondrial pathway is
characterized by caspase 9 activation, caspase 9 deletion does not prevent cell death 69.
Indeed, once a sufficient number of mitochondria have displayed MOMP, cell death is
caspase-independent 70. Since most oncogenic processes elicit a DNA damage response
which engages the mitochondrial pathway of cell death 71, cell death and elimination of the
potentially oncogenic cell should ensue whether or not caspases are inhibited. In contrast,
the extrinsic pathway is truly dependent on caspase 8 and, perhaps, caspase 10 72. For
example, the genetic absence of caspase 8 (mice do not express caspase 10) attenuates liver
injury in experimental murine models mediated by death ligands 72,73. Thus, caspase
inhibition should only reliably inhibit death receptor-mediated apoptosis, a common

mechanism of cell death in human liver diseases 17,74. As knockout murine models of
various death receptors do not develop spontaneous cancers, caspase inhibitors should prove
to be safe in man. However, more animal data in this regard would be reassuring.
There is considerable interest in developing short oligonucleotides rich in guanine residues

as inhibitors of TLR9 antagonists as immunomodulatory agents in immune-mediated
diseases such as systemic lupus erythematosis 75,76. Many of these compounds are salutary
in murine models of this disease. They have yet to be applied broadly to animal models of
fibrosis, and we await these studies with anticipation.
Acknowledgments
The secretarial help of Erin Nystuen-Bungum is gratefully acknowledged. We are indebted to prior post-doctoral
fellows who helped pioneer the relationship between apoptosis and fibrosis in the liver, especially Dr. Ali Canbay
who now has an independent laboratory program at University of Duisburg-Essen, Essen, Germany and Dr. Natalie
Torok, who also has an independent laboratory program at University of California Davis Medical Center,
Sacramento, CA. I also am appreciative of the expert aid of Steve Bronk in providing the graphic figures.
This work was supported by RO1 grants from the NIH, DK41876 and DK 63947, and the Mayo Foundation.
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Abbreviations Used
AIF Apoptosis-inducing factor

ALT Alanine transaminase
ATP Adenine triphosphate
Bcl-2 B-cell lymphoma-2
Bcl-xL B-cell lymphoma-2 like protein
CAD Caspase-activated DNase
Caspase Cysteine-dependent aspartate specific protease
CpG Cytosine-phosphate guanosine
DNA Deoxyribonucleic acid
ELISA Enzyme-linked immunosorbent assay
HBV Hepatitis B
HCV Hepatitis C
ICAD Inhibitor of caspase-activated DNase
Mcl-1 Myeloid cell leukemia-1

NASH Non-alcoholic steatohepatitis
P2Y2 Purinergic 2 Y2
SMAC/DIABLO Second mitochondria-derived activator of caspases/Direct IAP-
binding protein with low PI (DIABLO)
TLR9 Toll-like receptor 9
TNF Tumor necrosis factor
TRAIL TNF-related apoptosis-inducing ligand
TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling
UTP Uridine triphosphate

Figure 1. Cellular mechanisms linking hepatocyte apoptosis to liver fibrogenesis

Engulfment of apoptotic bodies by Kupffer cells enhances their expression of death ligands
which in a feed-forward loop further promote hepatocyte apoptosis and generation of
apoptotic bodies. Stellate cell or myofibroblast engulfment of apoptotic bodies enhances
their expression of collagen type 1 and TGFβ1, promoting development of fibrosis and
cirrhosis. Apoptotic cells also release the nucleotides UTP and ATP, which bind P2Y2
purinergic receptors on myofibroblasts further promoting collagen generation.

Figure 2. Activation of TLR9 by apoptotic body engulfment

The apoptotic bodies contain micronuclei with CpG DNA motifs. Following engulfment, the
apoptotic bodies are translocated into an endolysosome. This process triggers TLR9
trafficking from the endoplasmic reticulum (ER) to the endolysosome. The lower pH of the
endolysosome promotes TLR9 activation. The active receptor complex in stellate cells
results in transforming growth factor-beta (TGF-β) and collagen I production,60 whereas in

Kupffer cells it promotes interleukin-1β, a proinflammatory cytokine, generation 98

Figure 3. Therapeutic strategies to minimize liver disease progression

Apoptosis can be linked to hepatic fibrosis through engulfment of apoptotic bodies with
subsequent activation of TLR9 in stellate cells. Based on these concepts, inhibition of death
receptor-mediated apoptosis by caspase inhibitors should attenuate hepatic fibrosis.
Likewise, TLR9 inhibitors should prevent stellate cell activation despite engulfment of
apoptotic bodies thereby also reducing hepatic fibrogenesis.

Table I
Liver Cell Apoptosis in Human Liver Diseases
Liver Disease References
Chronic Viral Hepatitis 77-82
Acute Viral Hepatitis 83
Acute/Fulminant Hepatic Failure 84, 85
Alcohol-related Liver Disease 25,86,87
Non-alcoholic Steatohepatitis 27,87
Autoimmune Hepatitis 88
Primary Biliary Cirrhosis 89
Drug-induced Liver Injury

HCV-related Fibrosis 81
Wilson's Disease 90
Acute Allograft Rejection 91
Hepatocarcinoma 92, 93-97


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Semin Liver Dis. 2010 November ; 30(4): 402–410. doi:10.1055/s-0030-1267540.

Apoptosis as a Mechanism for Liver Disease Progression

Maria Eugenia Guicciardi, Ph.D. and Gregory J. Gores, M.D.

Mechanisms of Hepatocyte Apoptosis

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

endogenous cellular inhibitors of apoptosis proteins (IAPs), normally inhibiting accidentally

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

been shown to up-regulate DR5 expression and increase sensitivity of hepatocytes to

Apoptosis and Liver Fibrosis

the hepatocyte is constitutively undergoing pro-apoptotic stress, even in the absence of

Apoptotic Bodies and Their Engulfment

Apoptotic Bodies and The “Find Me” Signal

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Apoptotic Bodies and Liver Indigestion

If engulfment of apoptotic bodies is pro-fibrogenic, what in the apoptotic bodies is

Apoptosis and Anti-Fibrogenic Strategies for Human Liver Disease

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

patients, anti-apoptotic and anti-fibrogenic strategies have a hepatoprotective role. Two

inhibition should only reliably inhibit death receptor-mediated apoptosis, a common

There is considerable interest in developing short oligonucleotides rich in guanine residues

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

mitochondrial dysfunction and death. Science. 2001; 292(5517):727–730. [PubMed: 11326099]

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

966. [PubMed: 11915046]

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

alcoholic hepatitis. Hepatogastroenterology. 2003; 50(50):443–448. [PubMed: 12749243]

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

AIF Apoptosis-inducing factor

Mcl-1 Myeloid cell leukemia-1

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Figure 1. Cellular mechanisms linking hepatocyte apoptosis to liver fibrogenesis

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Figure 2. Activation of TLR9 by apoptotic body engulfment

results in transforming growth factor-beta (TGF-β) and collagen I production,60 whereas in

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Figure 3. Therapeutic strategies to minimize liver disease progression

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

Liver Disease References

Chronic Viral Hepatitis 77-82

Acute Viral Hepatitis 83

Acute/Fulminant Hepatic Failure 84, 85

Alcohol-related Liver Disease 25,86,87

Non-alcoholic Steatohepatitis 27,87

Primary Biliary Cirrhosis 89

Drug-induced Liver Injury

Acute Allograft Rejection 91

Hepatocarcinoma 92, 93-97

Semin Liver Dis. Author manuscript; available in PMC 2011 April 5.

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